Description:

The goal of the trial was to evaluate the timing of clopidogrel loading dose—prior to coronary angiography compared with in the catheterization laboratory only for patients who undergo percutaneous coronary intervention (PCI)—among patients undergoing elective coronary angiography for stable angina.

Hypothesis:

A 600 mg loading dose of clopidogrel at least 6 hours prior to PCI will result in a reduction in major adverse cardiac events.

Patient Populations:

Exclusions:

Thienopyridine treatment in the prior 2 weeks, contraindication for clopidogrel, coronary angiography scheduled <6 hours after potential randomization, clinically significant bleeding in the previous 3 months, or participation in another investigational drug or device trial in the preceeding month

Primary Endpoints:

Death, periprocedural MI, stroke, TIA, or reintervention within 7 days

Secondary Endpoints:

Troponin elevation more than 3 times the upper limit of normal, and major and minor bleeding

Drug/Procedures Used:

Patients were randomized in an open-label manner on the day prior to angiography to clopidogrel administration >6 hours prior to elective angiography (600 mg; n = 513) or delayed clopidogrel administration in the cath lab if needed for PCI (600 mg; n = 515).

Concomitant Medications:

At baseline, the use of aspirin was 7% versus 7% (p = 0.047), the use of anticoagulation was 6.5% versus 6% (p = 0.99), the use of a glycoprotein IIb/IIIa inhibitor was 0.2% versus 0.4% (p = 0.61), and the use of a statin was 57% versus 58% (p = 0.78) for nonselective clopidogrel versus selective clopidogrel, respectively.

Principal Findings:

PCI at the time of angiography was performed in 29% of patients (30% of the selective clopidogrel group and 28% of the nonselective group), and 12% of the patients underwent coronary artery bypass grafting, most of which was more than 7 days post-angiography. The remaining 59% of patients were managed medically.

There was no difference in the primary endpoint of death, periprocedural myocardial infarction (MI), stroke, transient ischemic attack (TIA), or reintervention within 7 days between the treatment groups whether evaluating all patients (0.8% in the nonselective arm and 1% in the selective arm, p = 0.75) or only patients who went on for PCI (1.3% in the nonselective clopidogrel group versus 2.8% in the selective clopidogrel group, p = 0.43). There was also no difference in the frequency of a periprocedural troponin elevation >3 times the upper limit of normal between the treatment groups in all patients (2.6% for nonselective clopidogrel versus 3.3% in the selective clopidogrel group, p = 0.48) or in the PCI cohort (8.4% versus 11.9%, respectively, p = 0.32).

Bleeding events were more frequent in the early, nonselective clopidogrel group than in the selective clopidogrel group overall (3.5% vs. 1.4%, p = 0.025) and in the PCI cohort (7.1% vs. 0.7%, p = 0.006).

Interpretation:

Among patients undergoing elective coronary angiography for stable angina, early routine use of clopidogrel loading more than 6 hours prior to angiography was not associated with a difference in the frequency of death, MI, stroke, TIA, or reintervention within 7 days when compared with selective use of clopidogrel during angiography if PCI is required, but was associated with a significant increase in bleeding complications.

Clopidogrel activation requires metabolization of the drug, with peak platelet inhibition requiring several hours to achieve. To increase the speed of activation, a loading dose is often given several hours before anticipated PCI. Rapid onset of platelet inhibition during PCI is important in the setting of an acute coronary syndrome such as ST-elevation MI.

The present study suggests that a routine loading dose is not required during elective, stable angiography, in which the majority of patients did not undergo revascularization. Even among patients who underwent PCI (~300 patients), there was no evidence of benefit with a loading dose administration. Conversely, bleeding complications increased in the setting of routine, early administration of clopidogrel.